1. Field of the Invention
This invention relates to interferon and in particular to vehicles for the topical and local administration of interferon.
2. Description of the Prior Art
In 1957, Isaacs and Lindenmann observed that supernatant fluids from virus-infected cell cultures contained an activity which could protect normal cells against infection by a wide variety of viruses. This activity was associated with a protein component which they called "interferon". Subsequently, it has been shown that there are various distinct types of interferon, generally classified as .alpha., .beta. and .gamma. interferons, which possess not only anti-viral activity, but also potent anti-cellular, anti-tumor and immunoregulatory activities.
.alpha. and .beta. interferons, also known as Type I interferons, are induced by viruses or synthetic polynucleotides acting on leukocyte and fibroblast cells, respectively. .gamma.-interferon, also known as immune or Type II interferon, is induced in primed lymphocytes by specific antigens or in umprimed lymphocytes by T-cell mitogens. All of these interferons have proved extremely difficult to purify to homogeneity and as a consequence are most often used as crude or partially purified preparations. General discussions of these interferons can be found in various texts and monographs, including The Interferon System, by W. E. Stewart, II, Springer-Verlag, New York (1979); Interferon 1981, Vol. 3, edited by Ion Gresser, Academic Press, New York (1981); and Interferon Therapy, World Health Organization Technical Reports Series 676, World Health Organization, Geneva, 1982.
For over a decade, interferons of all types have been employed in clinical trials. Originally, they were applied against viral pathogens, but subsequently their use has been extended to include treatment of a variety of malignant diseases. An important factor in the clinical application of interferons is the method of administration. Systemic administration, by either intravenous or intramuscular injection, has been used most frequently with some success. Among the problems inherent in this method of administration is that the interferon can come into contact with uninfected or nonmalignant cells and may cause unwanted side effects. Accordingly, the preferred approach would be to deliver interferon directly to the affected tissues or organs. In some cases, this can be accomplished by direct injection into the diseased site. In other cases, e.g., eye diseases and diseases like herpes genitalis, herpes labialis, herpes zoster and adenovirus induced keratitis and condyloma, all of which produce skin lesions, local topical application is the preferred method of administration. The present invention is concerned with this latter method of local administration.
The topical administration of interferon has proved to be a formidable problem for a number of reasons. First, interferon is a protein with a higher molecular weight than the molecular weights of therapeutic agents usually administered in topical preparations, e.g., porcaine, nitroglycerin, etc. In general, large molecular weight proteins have a much smaller solution diffusion coefficient than low molecular weight substances, a difference which generally becomes exacerbated in semi-solid media. Accordingly, the vehicle used to administer interferon locally must be able to hold the high molecular weight interferon in suspension during packaging, shipping and application, and yet also be able to release the interferon from the vehicle in a reasonable length of time once it has been applied at the diseased site. Second, the vehicle must not adversely affect the activity of the interferon by direct chemical action, precipitation or immobilization, any of which would preclude interaction of the interferon with the diseased site.
Third, and in many ways most difficult to achieve, the vehicle should allow the interferon preparation to have a sufficiently long shelf-life at room and body temperatures to allow for convenient shipping, handling and administration by the patient. In general terms, if a therapeutic agent is to be administered topically, the agent and its vehicle should satisfy the following shelf-life conditions: (1) the agent should retain a significant fraction of its therapeutic effect when held at room temperature (22.degree. C.) for a period of approximately fourteen days; and (2) the agent should also retain a significant fraction of its activity when held at body temperature (37.degree. C.) for a period of approximately one day. The fourteen day requirement at room temperature allows for shipping, handling and retailing of the preparation. The one day requirement at body temperature allows the patient to carry the product on his person and apply it throughout the day when needed.
Interferons produced by recombinant-DNA techniques or from natural sources when in a crude or partially purified form are notoriously temperature labile substances. For example, Moller, et al, reported at the Third Annual International Congress for Interferon Research that even at 4.degree. C., a human leukocyte interferon gel lost 80% of its activity in just two weeks. (Moller, B. R., Johannesen, P., Osther, K., Ulmsteen, U., Hastrup, J. and Berg, K., "Initial Evaluation of Topical Treatment of Dysplasia of the Cervical Epithelum with a Human Leukocyte Interferon Gel", Third Annual International Congress for Interferon Research, 1982.) Plainly, this is far from the fourteen days at 22.degree. C. and one day at 37.degree. C. stability requirements which an interferon preparation should achieve to satisfy commercial requirements. Presently available data suggest that highly purified interferons, in particular, highly purified .gamma.-interferon, may also be temperature labile. In view of this state of the art, it is clear that a vehicle for use in topically administering interferon has a heavy burden to carry in terms of providing a therapeutically stable preparation.